GABA A receptor changes in temporal lobo epilepsy

Temporal lobe epilepsy (TLE) represents about 40% of the epilepsies in the adult. Seizures generated by this disease are often resistant to common antiepileptic treatment, but in 80-90 % of therapy refractory patients they can be cured by unilateral surgical removal of parts of the hippocampus. Kainic acid-induced TLE in the rat represents a valuable animal model for human TLE. Upon injection of kainic acid, rats experience severe limbic seizures with status epilepticus. Although recovering physically from these seizures within a few days, the rats start to display spontaneous recurrent seizures after about three weeks. In addition to the clinical sequel, the neuropathological changes after kainic acid-induced seizures in the rat are strikingly similar to those observed in patients with TLE. Recently, dramatic changes in the expression of GABA A receptor subunits have been observed in kainic acid- induced TLE by our group. GABA (gamma-aminobutyric acid) is the major inhibitory transmitter in the nervous system, and most of the actions of GABA are mediated by GABA A receptors. GABA A receptor agonists such as benzodiazepines or barbiturates are potent anticonvulsive drugs and inhibition of these receptors causes convulsions. Changes in GABA A receptor expression or function might thus contribute to the development of TLE. Here, kainic acid-induced changes in GABA A receptor subunit expression, subunit composition and binding properties will be investigated in the dentate gyrus and the CA1 and CA3 region of the hippocampus, and in the amygdala, thalamus and entorhinal cortex at various timepoints after kainic acid injection, using biochemical, immunological, immunocytochemical, and in situ hybridization techniques. Some of these investigations will also be performed in hippocampal tissue from another animal model, the kindling model of TLE, and in hippocampal tissue surgically removed from patients with TLE. Combined, these studies will provide at a molecular level a comprehensive overview on changes in the composition of GABA A receptors in the course of TLE and will contribute to our understanding of mechanisms involved in the development of TLE and development of resistance to antiepileptic drug therapy. Finally, these data will be the basis for the generation of pharmacological strategies for a better antiepileptic treatment.

Temporal lobe epilepsy (TLE) represents about 40% of the epilepsies in the adult. Seizures generated by this disease are often resistant to common antiepileptic treatment, but in 80-90 % of therapy refractory patients they can be cured by unilateral surgical removal of parts of the hippocampus. Kainic acid-induced TLE in the rat represents a valuable animal model for human TLE. Upon injection of kainic acid, rats experience severe limbic seizures with status epilepticus. Although recovering physically from these seizures within a few days, the rats start to display spontaneous recurrent seizures after about three weeks. In addition to the clinical sequel, the neuropathological changes after kainic acid-induced seizures in the rat are strikingly similar to those observed in patients with TLE. Recently, dramatic changes in the expression of GABA A receptor subunits have been observed in kainic acid- induced TLE by our group. GABA (gamma-aminobutyric acid) is the major inhibitory transmitter in the nervous system, and most of the actions of GABA are mediated by GABA A receptors. GABA A receptor agonists such as benzodiazepines or barbiturates are potent anticonvulsive drugs and inhibition of these receptors causes convulsions. Changes in GABA A receptor expression or function might thus contribute to the development of TLE. Here, kainic acid-induced changes in GABA A receptor subunit expression, subunit composition and binding properties will be investigated in the dentate gyrus and the CA1 and CA3 region of the hippocampus, and in the amygdala, thalamus and entorhinal cortex at various timepoints after kainic acid injection, using biochemical, immunological, immunocytochemical, and in situ hybridization techniques. Some of these investigations will also be performed in hippocampal tissue from another animal model, the kindling model of TLE, and in hippocampal tissue surgically removed from patients with TLE. Combined, these studies will provide at a molecular level a comprehensive overview on changes in the composition of GABA A receptors in the course of TLE and will contribute to our understanding of mechanisms involved in the development of TLE and development of resistance to antiepileptic drug therapy. Finally, these data will be the basis for the generation of pharmacological strategies for a better antiepileptic treatment.